Multiple Sclerosis (MS) is a debilitating neurological disease which is partly heritable but it is clear that susceptibility to MS is also influenced by environmental factors or epigenetic mechanisms. It has been shown previously that N-acetyl-aspartate (NAA), a metabolite of neuronal mitochondria, is decreased in MS as measured by magnetic resonance imaging spectroscopy (MRI) and this decrease is correlated with disability. This observation suggests that neuronal mitochondria may be dysfunctional in MS. Mitochondria are particularly sensitive to environmental toxins and oxidative stress and therefore may be a target for the environmental component in MS neuronal pathology. For this reason it will be important to characterize mitochondria isolated from MS and control brain samples. Preliminary data indicates that mitochondria are different in MS cortex as compared to mitochondria isolated from the same cortical area in control cortex. This is a novel finding which may lead to new therapeutic targets for MS. The proposed studies are designed to understand how mitochondria differ in MS and to uncover mechanisms which may lead to dysfunctional mitochondria. These studies will involve generating mitochondrial protein profiles with Surface Enhanced Laser Desorption Ionization (SELDI) technology and two dimensional electrophoresis. These analyses will identify mitochondrial proteins that are differentially expressed and those that are oxidatively modified. The degeneration of axons and neurons in MS is the major factor contributing to MS disability. Neurons have an extremely high energy requirement in order to maintain ion homeostasis as a result of the ion fluxes which are a part of neurotransmission. Therefore they are particularly vulnerable to perturbations in energy production. We hypothesize that dysfunctional mitochondria in MS may play a role in neurodegeneration. The ultimate goal of the proposed research is to identify potential neuroprotective therapeutic targets for the treatment of MS. PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement Multiple sclerosis (MS) is both an autoimmune and a neurodegenerative disease. Therapies for MS target primarily the autoimmune component of the disease. These therapies have proven effective in reducing relapses and recently have been linked to slower disease progression. Ultimately, however, the progression of disability in MS is correlated with the loss of neurons and axons for which there are no current therapies available. For this reason, this proposal is focused on identifying differentially expressed and or modified mitochondrial proteins in the MS cortex. These studies will aid in the discovery of novel mechanisms involved in the neuropathology which occurs throughout the cortex and will potentially lead to the identification of new therapeutic targets for the treatment of MS.